DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

976 implicated in Reye’s syndrome and is the drug of choice
for antipyresis in children, teens, and young adults.
Concomitant NSAIDs and Low-Dose Aspirin. Many
patients combine either tNSAIDs or COX-2 inhibitors
with “cardioprotective,” low-dose aspirin. Epidemiological
studies suggest that this combination therapy increases significantly
the likelihood of GI adverse events over either
class of NSAID alone.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Prior occupancy of the active site of platelet COX-1 by the
commonly consumed tNSAID ibuprofen impedes access of aspirin
to its target Ser 529 and prevents irreversible inhibition of platelet
function (Catella-Lawson et al., 2001). Epidemiological studies have
provided conflicting data as to whether this adversely impacts clinical
outcomes, but they generally are constrained by the use of prescription
databases to examine an interaction between two drug
groups commonly obtained without prescription. Evidence in support
of this interaction has been observed in comparing ibuprofentreated
patients with and without aspirin in two coxib outcome
studies (CLASS and TARGET), but the trials were not powered to
address this question definitively. In theory, this interaction should
not occur with selective COX-2 inhibitors, because mature human
platelets lack COX-2. However, the GI safety advantage of NSAIDs
selective for COX-2 is lost when they are combined with low-dose
aspirin.
Drug Interactions
Angiotensin-converting enzyme (ACE) inhibitors act,
at least partly, by preventing the breakdown of kinins
that stimulate PG production. Thus, it is logical that
NSAIDs might attenuate the effectiveness of ACE
inhibitors by blocking the production of vasodilator and
natriuretic PGs. Due to hyperkalemia, the combination
of NSAIDs and ACE inhibitors also can produce
marked bradycardia leading to syncope, especially in
the elderly and in patients with hypertension, diabetes
mellitus, or ischemic heart disease. Corticosteroids and
SSRIs may increase the frequency or severity of GI
complications when combined with NSAIDs. NSAIDs
may augment the risk of bleeding in patients receiving
warfarin both because almost all tNSAIDs suppress
normal platelet function temporarily during the dosing
interval and because some NSAIDs also increase warfarin
levels by interfering with its metabolism; thus,
concurrent administration should be avoided. Many
NSAIDs are highly bound to plasma proteins and thus
may displace other drugs from their binding sites. Such
interactions can occur in patients given salicylates or
other NSAIDs together with warfarin, sulfonylurea
hypoglycemic agents, or methotrexate; the dosage of
such agents may require adjustment to prevent toxicity.
Patients taking lithium should be monitored because
certain NSAIDs (e.g., piroxicam) can reduce the renal
excretion of this drug and lead to toxicity, while others
can decrease lithium levels (e.g., sulindac).
Pediatric and Geriatric
Indications and Problems
Therapeutic Uses in Children. Therapeutic indications
for NSAID use in children include fever, mild pain,
postoperative pain, and inflammatory disorders, such
as juvenile arthritis and Kawasaki disease.
Inflammation associated with cystic fibrosis has
emerged as a potential indication for pediatric NSAID
use (Konstan et al., 1995); however, concern about GI
adverse effects has limited NSAID use for this indication.
The choice of drugs for children is considerably
restricted; only drugs that have been extensively tested
in children should be used (acetaminophen, ibuprofen,
and naproxen).
Kawasaki Disease. Aspirin generally is avoided in pediatric
populations due to its potential association with
Reye’s syndrome (see “Reye’s Syndrome”). However,
high doses of aspirin (30-100 mg/kg/day) are used to
treat children during the acute phase of Kawasaki disease,
followed by low-dose antiplatelet therapy in the
subacute phase. Aspirin is thought to reduce the likelihood
of aneurysm formation as a consequence of the
vasculitis particularly in the coronary arteries. Small
randomized studies did not conclusively show whether
aspirin adds benefit beyond the standard treatment of
Kawasaki disease with intravenous immunoglobulin
(Baumer et al., 2006).
Pharmacokinetics in Children. Despite the recognition that agedependent
differences in gastric emptying time, plasma protein binding
capacity and oxidative liver metabolism affect NSAID
pharmacokinetics in children, dosing recommendations frequently
are based on extrapolation of pharmacokinetic data from adults. The
majority of pharmacokinetic studies that were performed in children
involved patients >2 years of age, which often provide insufficient
data for dose selection in younger infants. For example, the pharmacokinetics
of the most commonly used NSAID in children, acetaminophen,
differ substantially between the neonatal period and older
children or adults. The systemic bioavailability of rectal acetaminophen
formulations in neonates and preterm babies is higher than in
older patients. Acetaminophen clearance is reduced in preterm
neonates probably due to their immature glucuronide conjugation
system (sulphatation is the principal route of biotransformation at
this age). Therefore, acetaminophen dosing intervals need to be
extended (8-12 hours) or daily doses reduced to avoid accumulation
and liver toxicity. Aspirin elimination also is delayed in neonates and
young infants compared to adults bearing the risk of accumulation.
Disease also may affect NSAID disposition in children. For
example, ibuprofen plasma concentrations are reduced and clearance
increased (~80%) in children with cystic fibrosis. This probably